Synthesis and deprotection of cyclic oxalate

Article abstract of DOI:10.14233/ajchem.2014.16373

As a new protective group for diols, cyclic oxalates [trans-1,2-cyclo-hexane diol 1,2-oxalate (1), 1,2:5,6-di-O-isopropylidene-D-mannitol 3,4-oxalate (2) and 1,2-propanediol 1,2-oxalate (3)] were synthesized by using oxalyl chloride, ethyloxalyl chloride,

Full text of DOI:10.14233/ajchem.2014.16373

Asian Journal of Chemistry; Vol. 26, No. 19 (2014), 6364-6366
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16373
Synthesis and Deprotection of Cyclic Oxalate
YUN-YOUNG KIM
Department of Chemistry, Dong-A University, 37 Nakdong-Daero 550 beon-gil, Saha-gu, Busan 604-714, Republic of Korea
Corresponding author: Tel: +82 51 2005627; E-mail: yoyoyokim@hanmail.net
Received: 14 September 2013;
Accepted: 17 June 2014;
Published online: 16 September 2014;
AJC-15918
As a new protective group for diols, cyclic oxalates [trans-1,2-cyclo-hexane diol 1,2-oxalate (1), 1,2:5,6-di-O-isopropylidene-D-mannitol
3,4-oxalate (2) and 1,2-propanediol 1,2-oxalate (3)] were synthesized by using oxalyl chloride, ethyloxalyl chloride, diethyl oxalate and
oxalic acid. Cyclic oxalates were readily cleaved to the corresponding diols by various bases such as sodium methoxide, potassium
carbonate, 1 % sodium hydroxide, triethylamine and lithium aluminium hydride, but were stable in acid.
Keywords: Cyclic oxalate, Polyhydroxy compound, Protection, deprotection, Protective group.
purified by the appropriate methods before use. Except where
explicitly stated, all the starting materials were purchased from
Aldrich, Fluka, Fisher, Lancaster, or TCI chemical companies
INTRODUCTION
In many preparations of delicate organic compounds,
some specific parts of their molecules cannot survive the required
reagents or chemical environments. Then, these parts or groups,
must be protected. The protective group must react selectively
in good yield to give a protected substrate that is stable to the
projected reactions. The protective group must be selectively
removed in good yield by readily available, preferably nontoxic
reagents that do not attack the regenerated functional group.
The protective group should form a crystalline derivative that
can be easily separated from side products associated with its
formation or cleavage. The protective group should have a
minimum of additional functionality to avoid further sites of
and used as received30,31
.
General synthesis of cyclic oxalate with oxalyl chloride:
A mixture of trans-1,2-cyclohexanediol (1 × 10-2 mol, 1.16 g)
and oxalyl chloride (1 × 10-2 mol, 1.18 mL) in pyridine (2 ×
10-2 mol, 1.54 mL) and CH2Cl2 (20 mL) solution was stirred
for 3 h. After 3 h, the reaction mixture was added CH2Cl2 (50
mL), water (30 mL) and 0.01 N HCl (20 mL). The combined
organic layers were dried over separated, anhydrous Na2SO4
filtered and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel eluted with ethyl
acetate and hexane, to provide trans-1,2-cyclohexanediol 1,2-
oxalate (67 %) and 1-O-carboxycarbonyl trans-1,2-cyclohexa-
nediol (25 %).
reaction1-17
.
Selective cleavage of protective groups in polyhydroxy
compounds are very useful in organic synthesis, especially in
the field of carbohydrate and nucleoside chemistry18-29
trans-1,2-Cyclohexanediol 1,2-oxalate (1): Rf : 0.45
(TLC eluent; ethyl acetate:chloroform:n-hexane = 2:1:4,
v/v/v); m.p. : 110-111 °C ; IR (KBr, νmax, cm-1) : 2960s (C-H),
1760s (C=O); 1H NMR (CDCl3) : δ 1.0-2.4 (m, 8H, CH2), 4.6-
4.73 (m, 2H, CH).
.
In this paper, we report the preparation of cyclic oxalate
by protection of 1,2-diol and 1,3-diol and the cleavage of cyclic
oxalate by treatment of acid and base.
EXPERIMENTAL
1,2:5,6-Di-O-isopropylidene-D-mannitol 3,4-oxalate
(2): Rf : 0.70 (TLC eluent; chloroform:methanol = 8:2, v/v);
m.p. : 143-144 °C ; IR (KBr, νmax, cm-1): 2980, 1790, 1760; 1H
NMR (CDCl3) : δ 1.4 (d, 12H, CH3), 4.0-4.5 (m, 8H, mannitol
CH).
Melting points were determined using an electrothermal
capillary melting point apparatus and uncorrected. Thin layer
chromatography (TLC) was performed on glass plates coated
with silicon oxide (silica gel 60F254) and compounds were
1
visualized using a UV lamp. H and 13C NMR spectra were
1,2-Propanediol 1,2-oxalate (3): Rf : 0.38 (TLC eluent;
ethyl acetate:chloroform:n-hexane = 2:1:3, v/v/v) ; m.p. : 119-
120 °C; IR (KBr, νmax, cm- 1): 2990s (C-H), 1762s, 1745s
(C=O), 1185s (C-O); 1H NMR (CDCl3) : δ 1.2 (d, 3H, CH3),
4.35 (d, 2H, CH2), 5.32 (m, 1H, CH).
obtained with Bruker AC2000 (200 MHz) and Varian Gemini
(200 or 300 MHz) spectrometers. Mass spectra were measured
with HP 5890 GC/Mass (70 eV, EI). The organic solvents and
chemicals were obtained from commercial products and

Vol. 26, No. 19 (2014)
Synthesis and Deprotection of Cyclic Oxalate 6365
1-O-Carboxycarbonyl trans-1,2-cyclohexanediol (4):
Rf: 0.20 (TLC eluent; methanol:methylene chloride = 3:7, v/v);
IR (KBr, νmax, cm-1): 3400s (O-H), 2920s (C-H), 1770s (C=O);
1H NMR (CDCl3): δ 1.0-1.8 (m, 8H, CH2), 3.5-4.0 (m, 1H,
OH), 4.6-5.0 (m, 2H, CH).
oxalate (3)] were synthesized by using oxalyl chloride,
ethyloxalyl chloride, diethyl oxalate and oxalic acid.
O
O
O
O
O
O
O
O
O
O
O
3-O-Carboxycarbonyl-1,2:5,6-di-O-isopropylidene-D-
mannitol (5): Rf : 0.09 (TLC eluent; chloroform:methanol =
8:2, v/v); m.p.: 120-122 °C; IR (KBr, νmax, cm-1): 3400, 1760,
1740; 1H NMR (Acetone-d6) : δ 1.35 (d, 12H, CH3), 2.5-3.0
(m, 2H, OH), 3.5-4.0 (m, 8H, mannitol CH).
O
O
O
O
O
1
3
2
trans-1,2-Cyclohexanediol 1,2-bis-ethyloxalate (6): Rf:
0.60 (TLC eluent; ethyl acetate:chloroform:n-hexane = 2:1:3,
v/v) ; IR (KBr, νmax, cm-1): 2970s (C-H), 1769s, 1745s (C=O),
1190s (C-O); 1H NMR (CDCl3) : δ 1.4 (t, 6H, CH2), 1.4-2.5
(m, 8H, CH2), 4.25 (q, 4H, OCH2), 4.8-5.15 (m, 2H, CH).
1,2:5,6-Di-O-isopropylidene-D-mannitol 3,4-bis-ethyl
oxalate (7): Rf: 0.74 (TLC eluent; benzene:acetone = 6:4, v/v);
IR (KBr, νmax, cm-1): 2980, 1760, 1740; 1H NMR (CDCl3) : δ
1.2 (m, 18H, CH3), 3.8-4.4 (m, 10H, mannitol CH, OCH2),
5.2-5.5 (dd, 2H, C3, 4H).
In the reaction of diols with oxalyl chloride, the product
was a mixture of the cyclic oxalates viz., trans-1,2-cyclohexanediol
1,2-oxalate (1) and 1,2:5,6-di-O-isopropylidene-D-mannitol
and mono oxalates viz., 1-O-carboxy-carbonyl trans-1,2-
cyclohexanediol (4) and 3-O-carboxycarbonyl-1,2:5,6-di-O-
isopropylidene-D-mannitol (5) and then the ratio of cyclic
oxalate and mono oxalate was 7:3.
O
O
C
O
C
O
O
O
OH
1,2-Propanediol 1,2-bis-ethyloxalate (8): Rf : 0.51 (TLC
eluent; ethyl acetate:chloroform:n-hexane = 2:1:3, v/v); IR
(KBr, νmax, cm-1): 2995s (C-H), 1775s, 1753s (C=O), 1200s
(C-O) ; 1H NMR (CDCl3) : δ 1.4 (dt, 9H, CH3), 4.35-4.4 (m,
6H, OCH2), 5.35 (m, 1H, CH).
C
O
C
O
OH
HO
O
OH
O
4
5
Methyl-α-D-glucopyranoside 2,3,4,6-tetraethyl oxalate
(9): Rf : 0.50 (TLC eluent; ethyl acetate:chloroform:n-hexane
= 2:2:3, v/v) ; IR (KBr, νmax, cm-1): 2935s (C-H), 1775s, 1748s
(C=O), 1183s (C-O); 1H NMR (CDCl3) : δ 1.30 (t, 12H, CH3),
3.29 (s, 3H, CH3), 4.23 (m, 11H, OCH2, C5H, C6H) 4.7-5.83
(m, 4H, C1H, C2H, C3H, C4H).
Whereas ethyl oxalyl chloride with triethylamine instead
of pyridine, cyclic oxalates [trans-1,2-cyclohexanediol 1,2-
oxalate (1), 1,2:5,6-di-O-isopropyl-idene-D-mannitol 3,4-
oxalate (2) and 1,2-propanediol 1,2-oxalate (3)] as well as acyclic
oxalates [trans-1,2-cyclohexanediol 1,2-bis-ethyloxalate (6),
1,2:5,6-di-O-isopropylidene-D-mannitol 3,4-bis-ethyloxalate
(7), 1,2-propanediol 1,2-bis-ethyloxalate (8), methyl-α-D-
glucopyranoside 2,3,4,6-tetraethyloxalate (9), 1-(2'-deoxy-β-
D-ribofuranosyl)-5-methyluracil 3',5'-bis-ethyloxalate (10) and
1,2,3-propanetriol 1,2-bis-ethyl oxalate (11)] were obtained.
1-(2'-Deoxy-β-D-ribofuranosyl)-5-methyluracil 3',5'-
bis-ethyl oxalate (10): Rf : 0.43 (TLC eluent; ethyl acetate:
methylene chloride = 5:3, v/v) ; IR (KBr, νmax, cm-1): 3190,
1
3050, 2993, 1750, 1700, 1190 ; H NMR (Acetone-d6) : δ
1.33 (t, 6H, CH3), 1.83 (s, 3H, CH3), 2.60 (m, 2H, C2H), 4.1-
4.7 (m, 5H, C3H, C5H, OCH2), 5.55 (m, 1H, C4H), 6.41 (t, 1H,
C1H), 7.67 (s, 1H, C6H).
O
O
OR
1,2,3-Propanetriol 1,2-bis-ethyl oxalate (11): Rf: 0.55
(TLC eluent; ethyl acetate:chloroform:n-hexane = 4:1:3, v/v);
IR (KBr, νmax, cm-1): 3410, 2990, 1760, 1748, 1190; 1H NMR
(CDCl3) : δ 1.4 (t, 6H, CH3), 4.43 (m, 10H, OCH2, glycerol
CH, OH).
OR
OR
OR
RO
O
OR
O
8
6
7
1,2,3-Propanetriol 1,3-diformate (12): Rf: 0.64 (TLC
eluent; ethyl acetate:chloroform:n-hexane = 4:1:3, v/v); IR
(KBr, νmax, cm-1): 3420, 2960, 1775, 1175; 1H NMR (CDCl3) : δ 3.2
(s, 1H, OH), 3.75 (d, 1H, CH), 4.2 (d, 4H, CH2), 8.1 (s, 2H,
CHO).
O
HN
CH3
CH2OR
HO
O
O
1,2-Propanetriol 1,3-diformate (13): Rf : 0.46 (TLC
eluent; ethyl acetate:chloroform:n-hexane = 5:1:2, v/v); IR
(KBr, νmax, cm-1): 2985, 1720, 1190; 1H NMR (CDCl3) : δ 1.25
(dt, 9H, CH3), 3.5-4.5 (d, 7H, C1,1',1'', 2'H), 5.3 (m, 2H, C2, 2''H),
8.1 (s, 2H, CHO).
N
OR
ROH2C
O
OR
OR
OR
OCH3
OR
RO
9
10
11
RESULTS AND DISCUSSION
As a new protective group for diols, cyclic oxalates [trans-
1,2-cyclo-hexane diol 1,2-oxalate (1), 1,2:5,6-di-O-isopro-
pylidene-D-mannitol 3,4-oxalate (2) and 1,2-propanediol 1,2-
O
O
C
C
OEt
-R
:

6366 Kim
Asian J. Chem.
2. L.D. Kohn and H.R. Kaback, J. Biol. Chem., 248, 7012 (1973).
Using diethyl oxalate, the amounts of cyclic oxalates
3. A. Merz, Angew. Chem. Int. Ed., 12, 846 (1973).
4. A.F. Kluge, K.G. Untch and J.H. Fried, J. Am. Chem. Soc., 94, 7827
(1972).
[trans-1,2- cyclohexanediol 1,2-oxalate (1) and 1,2-propane-
diol 1,2-oxalate (3)] were increased but there were some
difficulties in separation of its desired products.
5. E.J. Corey, J.-L. Gras and P. Ulrich, Tetrahedron Lett., 17, 809 (1976).
6. K.F. Bernady, M.B. Floyd, J.F. Poletto and M.J. Weiss, J. Org. Chem.,
44, 1438 (1979).
O
O
O
O
O
O
7. L. Lapatsanis, Tetrahedron Lett., 19, 3943 (1978).
8. H. Sommer and F. Cramer, Chem. Ber., 107, 24 (1974).
9. B.E. Cooper, Chem. Ind. (London), 794 (1978).
10. D.J. Ager and I. Fleming, J. Chem. Res. (S), 6 (1977).
11. H. Nakai, N. Hamanaka, J. Miyake and M. Hayashi, Chem. Lett., ooo,
1499 (1979).
O
O
12. E.S. Werstiuk and T. Neilson, Can. J. Chem., 50, 1283 (1972).
13. I. Watanabe, T. Tsuchiya, T. Takase, S. Umezawa and H. Umezawa,
Bull. Chem. Soc. Jpn., 50, 2369 (1977).
3
1
Oxalic acid, however did not afford cyclic oxalates but
gave formates which probably were formed by decarboxylation
of hydroxyoxalyl group.
14. A.I. Meyers, K. Tomioka, D.M. Roland and D. Comins, Tetrahedron
Lett., 19, 1375 (1978).
15. E.J. Corey and J.W. Suggs, J. Org. Chem., 38, 3223 (1973).
16. K.I. Agarwal and H.G. Khorana, J. Am. Chem. Soc., 94, 3578 (1972).
17. A.A. Nagel and L.A. Vincent, J. Org. Chem., 44, 2050 (1979).
18. Y. Kamaya and T. Higuchi, FEMS Microbiol. Lett., 24, 225 (1984).
19. Z. Moussa, and D. Romo, Synlett, 3294 (2006).
20. J. Romanski, P. Nowak, K. Kosinski and J. Jurczak, Tetrahedron Lett.,
53, 5287 (2012).
O
OCH
O
OCH
O O
O
21. J. Clayden, N. Greeves and S. Warren, Organic Chemistry, edn 2, pp.
1264 (2012).
O-C-C-O
OH
OCH
22. W.C. Chan and P.D. White, Fmoc Solid Phase Peptide Synthesis, Ox-
ford University press (2004).
OCH
O
O-C-C-O
O O
23. W.C. Chan and P.D. White, Fmoc Solid Phase Peptide Synthesis: A
Practical Approach, Oxford University Press, pp. 10-12 (2000).
24. R.B. Merrifield, G. Barany, W.L. Cosand, M. Engelhard and S. Mojsov,
Proc. Am. Pept. Symp. 5th (1977).
13
12
25. A. Blanc and C.G. Bochet, Org. Lett., 9, 2649 (2007).
26. P.S. Baran, T.J. Maimone and J.M. Richter, Nature, 446, 404 (2007).
27. H. Muratake, H. Kumagami and M. Natsume, Tetrahedron, 46, 6351
(1990).
Cyclic oxalates were readily cleaved to the corresponding
diols by various bases such as sodium methoxide, potassium
carbonate, 1 % sodium hydroxide, triethylamine and lithium
aluminium hydride, but were stable in acid.
28. H. Muratake and M. Natsume, Tetrahedron, 46, 6331 (1990).
29. H. Muratake and M. Natsume, Tetrahedron, 46, 6343 (1990).
30. J.A. Riddick and W.B. Bunger, Organic Solvents, edn. 5, Wiley-
Interscience, New York (1970).
REFERENCES
31. F.A. Carey and R.J. Sundberg, Advanced Organic Chemistry, Springer,
Part 2, edn 5, pp. 433-437 (2008).
1. T.W. Green, Protective Groups in Organic Synthesis, John Wiley &
Sons. Inc., New York, pp. 1-4 (1981).